Diarylcuprates for Selective Syntheses of Multifunctionalized Ketones from Thioesters under Mild Conditions

Abstract

Ketones were selectively synthesized from thioesters by using diarylcuprates(I) generated in situ from copper(I) salts and aryl Grignard reagents in a 1 : 1.3–1.5 ratio under ambient temperature. During the ketone synthesis, various functional groups, such as carbonyl (ketones, esters, and amides), O‐protecting groups, halogens, and heteroarenes, were tolerated to afford multifunctionalized ketones in excellent yields. This copper‐mediated ketone synthesis could be applied to the synthesis of not only gluconolactone‐derived ketone 6, a synthetic intermediate in the transformation to the SGLT2 inhibitor canagliflozin, but also thiolactol 8, a valuable synthetic intermediate for (+)‐biotin. Control experiments on an isolated diphenylcuprate(I), [CuPh2]− (12), and DFT calculations revealed that this ketone synthesis proceeded by oxidative addition of the C−S bond of thioesters to [CuPh2]−, while reductive elimination from the CuIII intermediate produced the corresponding ketone and an inactive species [(RS)CuPh]−, the latter reacted with [CuPh]4 (11) to regenerate the reactive diphenylcuprate(I).

Synthesis of (−)-Cotylenol, a 14-3-3 Molecular Glue Component

“…4-Chloro substitution on the thioester was necessary to achieve a good yield, whereas the parent phenyl thioester led to a low yield and low conversion of the C-ring electrophile. Whereas Cu­(I)-mediated couplings of thioesters with hard organometallic nucleophiles have seen significant development, their use in the convergent coupling of highly functionalized or hindered fragments is scarce …”